Stem cells in the adult heart - 3D culture, isolation of side population cells and search for a stem cell niche
Abstract
Cardiac tissue shows a poor regenerative capacity. From 2003 reports, mostly based
on animal models, have showed existence of stem cells also in the heart. Using 14C
measurements, a slow but steady turnover of the cardiac cells was shown in
humans, around 1%/year. As a source for this regeneration endogenous stem cells
have been suggested.
The aim of this thesis was to identify, isolate and characterize cardiac stem cells
and to find their niche. Therefore, in Study I a new “High Density Sphere” 3D
culture system was adopted where cardiac- and progenitor biomarker levels
increased over time. In Study II Side Population progenitors were isolated from
the left human atria. In Study III the distribution of label retaining cells was
investigated, throughout the adult rat heart and a region in the Atrio Ventricular
junction (AVj) was proposed as a potential stem cell niche. To assess translatability
human AVj was explored in Study IV. The concomitant appearance of all of the
selected stem cell biomarkers in the AVj indicated that the normal human heart
also harbors a potential stem cell niche which to our knowledge has not been
described previously. The location of these findings in the humans coincides with
the same region in rat hearts.
In conclusion we propose a new, 3D in vitro system for studies of cardiac cell
phenotypes, identified Side Population cells and found an anatomic site, with
features of a stem cell niche in rats and humans. The function of these potential
niches is important to investigate in future. With these findings, we hope to
contribute to better understanding of basic concepts of cardiac regeneration; an
important step towards improved future therapies for patients.
Parts of work
I. High density sphere culture of adult cardiac cells increases the levels of cardiac and progenitor markers and shows signs of vasculogenesis.
Vukusic K, Jonsson M, Brantsing C, Dellgren G, Jeppsson A, Lindahl A. and Asp J. BioMed Research International 2013; 696837 ::PMID::23484142 II. Left atrium of the human adult heart contains a population of side population cells. Sandstedt J, Jonsson M, Kajic K, Sandstedt M, Lindahl A, Dellgren G, Jeppsson A and Asp J. Basic research in cardiology 2012 Mar; 107(2):255 ::PMID::22361742 III. Physical exercise affects slow cycling cells in the rat heart and reveals a new potential niche area in the atrioventricular junction. Vukusic K, Asp J, Henriksson HB, Brisby H, Lindahl A and Sandstedt J.
Journal of Molecular Histology 2015 Oct; 46(4-5):387-98 ::PMID::26047663 IV. Atrioventricular junction of the human adult heart harbours stem cells, different stages of cardiomyocytes and shows signs of hypoxia, proliferation and migration.
Vukusic K, Jansson M, Jonsson M, Sandstedt M, Oldfors A, Jeppsson A, Dellgren G. Lindahl A and Sandstedt J.
in Manuscript
Degree
Doctor of Philosophy (Medicine)
University
University of Gothenburg. Sahlgrenska Academy
Institution
Institute of Biomedicine. Department of Clinical Chemistry and Transfusion Medicine
Disputation
Fredagen den 17 november 2017, kl. 13.00, Hörsal Arvid Carlsson, Academicum, Medicinaregatan 3, Göteborg
Date of defence
2017-11-17
kristina.vukusic@gu.se
Date
2017-10-26Author
Vukusic, Kristina
Keywords
Heart
cardiac stem cells
Stem cell niche
Atrioventricular junction
Side population
3D culture
Publication type
Doctoral thesis
ISBN
978-91-629-0231-5 (PRINT)
978-91-629-0230-8 (TRYCK)
Language
eng